Obligatory role for GPER in cardiovascular aging and disease

Abstract

Pharmacological activation of the heptahelical G protein-coupled estrogen receptor (GPER) by selective ligands counteracts multiple aspects of cardiovascular disease. We thus expected that genetic deletion or pharmacological inhibition of GPER would further aggravate such disease states, particularly with age. To the contrary, we found that genetic ablation of Gper in mice prevented cardiovascular pathologies associated with aging by reducing superoxide (O2-) formation byNADPHoxidase (Nox) specifically through reducing the expression of the Nox isoformNox1.BlockingGPER activity pharmacologicallywith G36, a synthetic, small-molecule, GPER-selective blocker (GRB), decreased Nox1 abundance and O2 - production to basal amounts in cells exposed to angiotensin II and in mice chronically infused with angiotensin II, reducing arterial hypertension. Thus, this study revealed a role for GPER activity in regulating Nox1 abundance and associated O2 -mediated structural and functional damage that contributes to disease pathology. Our results indicated that GRBs represent a new class of drugs that can reduce Nox abundance and activity and could be used for the treatment of chronic disease processes involving excessive O2 - formation, including arterial hypertension and heart failure.